Rapamycin is also called as Sirolimus, and was separated and obtained from Streptomyces hygroscopicus by Veniza et al in 1975. In 1989, Rapamycin entered clinical phase as a new immunosuppressor, and it was marketed in 1999. Later, the inhibition effect of rapamycin on T lymphocyte proliferation teaches using it to inhibit cancer cells, and it is found that it shows good antineoplastic activity, and this compound as an anticancer drug has been developed by Wyeth Company of the USA and is about to enter clinic phase.
The acting target of rapamycin in human body is mTOR (mammal rapamycin target protein). mTOR is an important component of PI3K-Akt-mTOR signal pathway. PI3K-Akt-mTOR signal pathway regulates proliferation- and apoptosis-related signal transduction pathways of tumor cells, so that on the one hand, proliferative activity of tumor cells is promoted to further enhance infiltration and metastasis abilities of tumor cells; and on the other hand, the acts on tumor apoptosis-related proteins promote activation of endogenous apoptosis inhibitors and/or expression and activation of apoptosis-inhibition-related protein kinases, thereby inhibiting apoptosis of tumor cells. Hence, PI3K-Akt-mTOR signal pathway may be the regulation core for tumor occurrence and development, so that mTOR is a key target for gene therapy of tumors.
In animal body, mTOR exists mainly in two complex forms, i.e., mTORC1 and mTORC2, in which mTORC1 (mTOR complex 1) consists of 4 parts: mTOR, raptor (regulatory associated protein of mTOR), mLST8, PRAS40 (Proline-rich AKT Substrate 40 kDa); while mTORC2 (mTOR complex2) consists of 5 parts: mTOR, rictor (raptor independent), mLST8, mSIN1 (mammalian stress-activated protein kinase interacting protein 1), Protor-1 (Proteinobserved with rictor-1). mTORC1 and mTORC2 involves almost all different upstream activators and downstream effectors, and they mutually harmonize and regulate together cell cycle progression. The downstream effectors of mTORC1 mainly include ribosome p70S6 kinase protein (S6 kinase 1, S6K1) and eukaryotic initiation factor 4E binding protein 1(4EBP1). By regulating 4EBP1 and S6K1 phosphorylation, mTORC1 influences translation initiation of specific mRNA, thereby regulating protein synthesis and regulating cell growth and proliferation, in which its major biological function is to regulate protein synthesis. When mTORC1 is stimulated by a factor such as a growth factor, it can promote cell growth and proliferation via activating downstream S6K1 (Thr389 site). Once mTORC1 in vivo is over-activated, downstream 4EBP1 and S6K1 would overexpressed, and then cell proliferation is out of control, and then excessive immune or cancers would occur. mTORC2 mainly takes part in construction of cytoskeletal proteins, and mTORC2 can upregulate Akt level via acting on Ser473 site of Akt. (TANG Yan, Research summary of mTOR inhibitors [J]. Organic Chemistry, 2011, 31(7): 1144-1154.) The immunosuppression and antitumor mechanisms of rapamycin are mainly to inhibit mTORC1 via binding to cell receptor FKBP12, but rapamycin has very slight inhibition effects on mTORC2.

Although rapamycin has potent anticancer activity, it has two severe defects: poor stability and poor water solubility. Rapamycin has a solubility of only 2.6 μg/ml in water, i.e., it is almost insoluble in water. After many years of research, it is found that modification of hydroxy at position 42 of rapamycin is a reliable way to improve physical and chemical properties of rapamycin, and some drugs in markets are based on this scheme.
Some rapamycin derivatives with position 42 substituted in markets are listed as follows:
Temsirolimus, of which the trade name is Torisel, is developed by Wyeth-Ayerst, and it is a rapamycin derivative with 42-acrylate, and is a prodrug of rapamycin. It is the earliest anticancer drug among rapamycin derivatives approved by FDA (2007). Temsirolimus is a first-line drug for treatment of advanced renal cell carcinoma (RCC) in patients, and it could extend median survival time by 3-6 months in early RCC patients. Temsirolimus can significantly inhibit T cell proliferation, its median inhibitory concentration (IC50) is 0.8 nmol/L, and it can be used in combination with kinase inhibitors such as Sunitinib or Sorafenib.
Everolimus, of which the trade name is Zortress, is developed by Novartis Company, and is the first oral mTOR inhibitor, its chemical structure is 42-O-(2-hydroxyethyl)-rapamycin, the water solubility is superior to rapamycin, and it is rapidly hydrolyzed after entering human body. Experiments show that Everolimus has oral bioavailability of merely 15%-30%, and half-life of 16-19 h in human body. It firstly came into the market in Sweden in 2003, initially acted as only an immunosuppressor, and now it is approved to treat RCC, pancreatic neuroendocrine tumor (PNET) and subependymal giant cell astrocytoma (SEGA). FDA has approved that Everolimus oral tablets can be used for preventing adult kidney transplantation patients with lower or moderate immune risk from organ rejection response. Everolimus can be used simultaneously in combination with amount-reduced cyclosporine A and basiliximab and corticosteroids. The approved phase III test showed that Everolimus can prevent acute organ rejection and hold kidney function.
Ridaforolimus (Ariad/Merck Company) has modification at C43-position of rapamycin, which improves its solubility and PK value. As for its research work, its phase-III clinic test in treatment of metastatic soft-tissue or bone sarcomas had been completed. In comparison with placebo group, medication group had a mortality risk which was reduced by 28% (NCT00538239). In 2012, Ariad and Merck Company filed with FDA a new drug application of ridaforolimus, but FDA expert panel had doubt in its therapeutic effects, and thus there were some obstruction in application.
Zotarolimus (Medtroni Company) was approved by FDA in 2006 in Zotarolimus-coated coronary stent system (Endeavor), and in comparison with the bare-metal coronary stent group, the drug-coated group could effectively reduce death rate of arterial embolism, heart diseases and myocardial infarction in stent users.
Umiroliums (Biolimus, Biosensors Company) was approved in Europe in 2007 in Biolimus-coated coronary stent system, biolimus A9. It is more potent than rapamycin in terms of immunosuppression and anti-inflammatory activity, and it binders cell migration and proliferation by cell cycle arrest at G1, thereby preventing occurrence of vascular restenosis.
At present, it is still in need to develop new rapamycin derivatives.